Steady and ranging sets in graph persistence

Generalised persistence functions (gp-functions) are defined on $(\mathbb{R}, \le)$-indexed diagrams in a given category. A sufficient condition for stability is also introduced. In the category of graphs, a standard way of producing gp-functions is proposed: steady and ranging sets for a given feature. The example of steady and ranging hubs is studied in depth; their meaning is investigated in three concrete networks

Characteristics of Social Entrepreneur: An Explorative Analysis

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Modulation of tumor angiogenesis by conditional expression of fibroblast growth factor-2 affects early but not established tumors.

Fibroblast growth factor-2 (FGF2) is a pleiotropic heparin-binding growth factor endowed with a potent angiogenic activity in vitro and in vivo. To investigate the impact of the modulation of FGF2 expression on the neovascularization at different stages of tumor growth, we generated stable transfectants (Tet-FGF2) from the human endometrial adenocarcinoma HEC-1-B cell line in which FGF2 expression is under the control of the tetracycline-responsive promoter (Tet-off system). After transfection, independent clones were obtained in which FGF2 mRNA and protein were up-regulated compared with parental cells. Also, the conditioned medium of Tet-FGF2 transfectants caused proliferation, urokinase-type plasminogen activator up-regulation, migration, and sprouting of cultured endothelial cells. A 3-day treatment of Tet-FGF2 cell cultures with tetracycline abolished FGF2 overexpression and the biological activity of the conditioned medium without affecting their proliferative capacity. Tet-FGF2 cells formed tumors when nude mice received s.c. injections. The administration of 2.0 mg/ml tetracycline in the drinking water before cell transplantation, continued throughout the whole experiment, inhibited FGF2 expression in Tet-FGF2 tumor lesions. This was paralleled by a significant decrease in the rate of tumor growth and vascularization to values similar to those observed in lesions generated by parental HEC-1-B cells. Tetracycline administration 20 days after tumor cell implant, although equally effective in reducing FGF2 expression and inhibiting tumor vascularity, only minimally impaired the growth of established Tet-FGF2 tumors. The results indicate that FGF2 expression deeply affects the initial tumor growth and neovascularization of HEC-1-B human endometrial adenocarcinoma in nude mice. On the contrary, the growth of established tumors appears to be independent of the inhibition of FGF2 expression and decreased vascular density. The possibility that a significant reduction of angiogenesis may not affect the progression of large tumors points to the use of antiangiogenic therapy in early tumor stage

Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer.

The epidermal growth factor receptor (EGFR), a member of the ErbB family of receptor tyrosine kinases, is expressed in up to 70% of epithelial ovarian cancers (EOCs), where it correlates with poor prognosis. The majority of EOCs are diagnosed at an advanced stage, and at least 50% present malignant ascites. High levels of IL-6 have been found in the ascites of EOC patients and correlate with shorter survival. Herein, we investigated the signaling cascade led by EGFR activation in EOC and assessed whether EGFR activation could induce an EOC microenvironment characterized by pro-inflammatory molecules. In vitro analysis of EOC cell lines revealed that ligand-stimulated EGFR activated NFkB-dependent transcription and induced secretion of IL-6 and plasminogen activator inhibitor (PAI-1). IL-6/PAI-1 expression and secretion were strongly inhibited by the tyrosine kinase inhibitor AG1478 and EGFR silencing. A significant reduction of EGF-stimulated IL-6/PAI-1 secretion was also obtained with the NFkB inhibitor dehydroxymethylepoxyquinomicin. Of 23 primary EOC tumors from advanced-stage patients with malignant ascites at surgery, 12 co-expressed membrane EGFR, IL-6 and PAI-1 by immunohistochemistry; both IL-6 and PAI-1 were present in 83% of the corresponding ascites. Analysis of a publicly available gene-expression data set from 204 EOCs confirmed a significant correlation between IL-6 and PAI-1 expression, and patients with the highest IL-6 and PAI-1 co-expression showed a significantly shorter progression-free survival time (P=0.028). This suggests that EGFR/NFkB/IL-6-PAI-1 may have a significant impact on the therapy of a particular subset of EOC, and that IL-6/PAI-1 co-expression may be a novel prognostic marker

Neuronal Antibodies and Brain alterations in APECED Patients

APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Distrophy) is a rare autosomal recessive disorder. We previously found that sera samples from 9/14 patients revealed autoantibodies (Auto-Abs) reacting with cerebellum (GABAergic cells, n=5) and substantia nigra (SN; dopaminergic cells, n=5) [1]. Follow-up of the large majority of these patients was perfomed at least 10 years after the previous investigation. Indeed, on these patients, and on control age-matched subjects (n=14), we performed brain examinations using an MRI scanner. Obtained images were used to evaluate the volumes of white and gray matter (W.M and G.M., respectively) as well as the ventricles (III and IV). In addition, we used immunohistochemistry (IHC) on tissues from rat brain (after perfusion with 4% paraformaldehyde) in order to confirm the previous immunoreactivities or found new Auto-Abs cell targets. The brain MR revealed a reduction of G.M (p = 0.042) and cerebellum (p = 0.0012), and an increase of ventricles (p = 0.0001), compared to controls. Through IHC, after 10 years, we found 11/14 patients producing Auto-Abs against different brain neuronal cells. In detail, among the patients previously investigated and containing Auto-Abs against GABAergic perikarya in the cerebellum, 3 still contained the same immunoreactivity while 1 was unavailable, and 1 lost the reactivity. Instead, as to Auto-Abs against dopaminergic perikarya in the SN, 4 patients confirmed their previous reactivity, while 3 previously negative patients, revealed novel positivity (in total, n=7). A new immunoreactivity against the 5HT cells in the brainstem were also revealed in the same patients with Auto-Abs to SN (n=7). In conclusion, the co-presence of brain volume changes and neuronal Auto-Abs in APECED patients could suggest an autoimmune manifestation at the brain level that should be taken in consideration

Functional and pharmacological evaluation of novel GLA variants in Fabry disease identifies six (two de novo) causative mutations and two amenable variants to the chaperone DGJ

Abstract Background Allelic heterogeneity is an important feature of the GLA gene for which almost 900 known genetic variants have been discovered so far. Pathogenetic GLA variants cause alpha-galactosidase A (α-Gal A) enzyme deficiency leading to the X-linked lysosomal storage disorder Fabry disease (FD). Benign GLA intronic and exonic variants ( e.g. pseudodeficient p.Asp313Tyr) have also been described. Some GLA missense variants, previously deemed to be pathogenetic ( e.g. p.Glu66Gln and p.Arg118Cys), they have been reclassified as benign after re-evaluation by functional and population studies. Hence, the functional role of novel GLA variants should be investigated to assess their clinical relevance. Results We identified six GLA variants in 4 males and 2 females who exhibited symptoms of FD: c.159C>G p.(Asn53Lys), c.400T>C p.(Tyr134His), c.680G>C (p.Arg227Pro), c.815A>T p.(Asn272Ile), c.907A>T p.(Ile303Phe) and c.1163_1165delTCC (p.Leu388del). We evaluated their impact on the α-Gal A protein by bioinformatic analysis and homology modelling, by analysis of the GLA mRNA, and by site-directed mutagenesis and in vitro expression studies. We also measured their responsiveness to the pharmacological chaperone DGJ. Conclusions The six detected GLA variants cause deficient α-Gal A activity and impairment or loss of the protein wild-type structure. We found p.Asn53Lys and p.Ile303Phe variants to be susceptible to DGJ

POLARIX: a pathfinder mission of X-ray polarimetry

Since the birth of X-ray astronomy, spectral, spatial and timing observation improved dramatically, procuring a wealth of information on the majority of the classes of the celestial sources. Polarimetry, instead, remained basically unprobed. X-ray polarimetry promises to provide additional information procuring two new observable quantities, the degree and the angle of polarization. POLARIX is a mission dedicated to X-ray polarimetry. It exploits the polarimetric response of a Gas Pixel Detector, combined with position sensitivity, that, at the focus of a telescope, results in a huge increase of sensitivity. Three Gas Pixel Detectors are coupled with three X-ray optics which are the heritage of JET-X mission. POLARIX will measure time resolved X-ray polarization with an angular resolution of about 20 arcsec in a field of view of 15 arcmin $\times$ 15 arcmin and with an energy resolution of 20 % at 6 keV. The Minimum Detectable Polarization is 12 % for a source having a flux of 1 mCrab and 10^5 s of observing time. The satellite will be placed in an equatorial orbit of 505 km of altitude by a Vega launcher.The telemetry down-link station will be Malindi. The pointing of POLARIX satellite will be gyroless and it will perform a double pointing during the earth occultation of one source, so maximizing the scientific return. POLARIX data are for 75 % open to the community while 25 % + SVP (Science Verification Phase, 1 month of operation) is dedicated to a core program activity open to the contribution of associated scientists. The planned duration of the mission is one year plus three months of commissioning and SVP, suitable to perform most of the basic science within the reach of this instrument.Comment: 42 pages, 28 figure

In-hospital percentage BNP reduction is highly predictive for adverse events in patients admitted for acute heart failure: the Italian RED Study

Introduction: Our aim was to evaluate the role of B-type natriuretic peptide (BNP) percentage variations at 24 hours and at discharge compared to its value at admission in order to demonstrate its predictive value for outcomes in patients with acute decompensated heart failure (ADHF). Methods: This was a multicenter Italian (8 centers) observational study (Italian Research Emergency Department: RED). 287 patients with ADHF were studied through physical exams, lab tests, chest X Ray, electrocardiograms (ECGs) and BNP measurements, performed at admission, at 24 hours, and at discharge. Follow up was performed 180 days after hospital discharge. Logistic regression analysis was used to estimate odds ratios (OR) for the various subgroups created. For all comparisons, a P value 46% at discharge had an area under curve (AUC) of 0.70 (P 300 pg/mL. A BNP reduction of 25.9% after 24 hours had an AUC at ROC curve of 0.64 for predicting adverse events (P 46% was 4.775 (95% confidence interval (CI) 1.76 - 12.83, P 300 pg/mL and whose percentage decrease at discharge was 46% was 9.614 (CI 4.51 - 20.47, P 46% at hospital discharge compared to the admission levels coupled with a BNP absolute value < 300 pg/mL seems to be a very powerful negative prognostic value for future cardiovascular outcomes in patients hospitalized with ADHF

The DivJ, CbrA and PleC system controls DivK phosphorylation and symbiosis in Sinorhizobium meliloti

Sinorhizobium meliloti is a soil bacterium that invades the root nodules it induces on Medicago sativa, whereupon it undergoes an alteration of its cell cycle and differentiates into nitrogen-fixing, elongated and polyploid bacteroid with higher membrane permeability. In Caulobacter crescentus, a related alphaproteobacterium, the principal cell cycle regulator, CtrA, is inhibited by the phosphorylated response regulator DivK. The phosphorylation of DivK depends on the histidine kinase DivJ, while PleC is the principal phosphatase for DivK. Despite the importance of the DivJ in C. crescentus, the mechanistic role of this kinase has never been elucidated in other Alphaproteobacteria. We show here that the histidine kinases DivJ together with CbrA and PleC participate in a complex phosphorylation system of the essential response regulator DivK in S. meliloti. In particular, DivJ and CbrA are involved in DivK phosphorylation and in turn CtrA inactivation, thereby controlling correct cell cycle progression and the integrity of the cell envelope. In contrast, the essential PleC presumably acts as a phosphatase of DivK. Interestingly, we found that a DivJ mutant is able to elicit nodules and enter plant cells, but fails to establish an effective symbiosis suggesting that proper envelope and/or low CtrA levels are required for symbiosis.National Institutes of Health (U.S.) (Grant GM31010